SummaryThe project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.

The project outlined here addresses the fundamental question how the brain encodes and controls behavior. While we have a reasonable understanding of the role of entire brain areas in such processes, and of mechanisms at the molecular and synaptic levels, there is a big gap in our knowledge of how behavior is controlled at the level of defined neuronal circuits.
In natural environments, chances for survival depend on learning about possible aversive and appetitive outcomes and on the appropriate behavioral responses. Most studies addressing the underlying mechanisms at the level of neuronal circuits have focused on aversive learning, such as in Pavlovian fear conditioning. Understanding how activity in defined neuronal circuits mediates appetitive learning, as well as how these circuitries are shared and interact with aversive learning circuits, is a central question in the neuroscience of learning and memory and the focus of this grant application.
Using a multidisciplinary approach in mice, combining behavioral, in vivo and in vitro electrophysiological, imaging, optogenetic and state-of-the-art viral circuit tracing techniques, we aim at dissecting the neuronal circuitry of appetitive Pavlovian conditioning with a focus on the amygdala, a key brain region important for both aversive and appetitive learning. Ultimately, elucidating these mechanisms at the level of defined neurons and circuits is fundamental not only for an understanding of memory processes in the brain in general, but also to inform a mechanistic approach to psychiatric conditions associated with amygdala dysfunction and dysregulated emotional responses including anxiety and mood disorders.

Max ERC Funding

2 497 200 €

Duration

Start date: 2016-01-01, End date: 2020-12-31

Project acronymBrain circRNAs

ProjectRounding the circle: Unravelling the biogenesis, function and mechanism of action of circRNAs in the Drosophila brain.

Researcher (PI)Sebastian Kadener

Host Institution (HI)THE HEBREW UNIVERSITY OF JERUSALEM

Call DetailsConsolidator Grant (CoG), LS5, ERC-2014-CoG

SummaryTight regulation of RNA metabolism is essential for normal brain function. This includes co and post-transcriptional regulation, which are extremely prevalent in neurons. Recently, circular RNAs (circRNAs), a highly abundant new type of regulatory non-coding RNA have been found across the animal kingdom. Two of these RNAs have been shown to act as miRNA sponges but no function is known for the thousands of other circRNAs, indicating the existence of a widespread layer of previously unknown gene regulation.
The present proposal aims to comprehensively determine the role and mode of actions of circRNAs in gene expression and RNA metabolism in the fly brain. We will do so by studying their biogenesis, transport, and mechanism of action, as well as by determining the roles of circRNAs in neuronal function and behaviour. Briefly, we will: 1) identify factors involved in the biogenesis, localization, and stabilization of circRNAs; 2) determine neuro-developmental, molecular, neural and behavioural phenotypes associated with down or up regulation of specific circRNAs; 3) study the molecular mechanisms of action of circRNAs: identify circRNAs that work as miRNA sponges and determine whether circRNAs can encode proteins or act as signalling molecules and 4) perform mechanistic studies in order to determine cause-effect relationships between circRNA function and brain physiology and behaviour.
The present proposal will reveal the key pathways by which circRNAs control gene expression and influence neuronal function and behaviour. Therefore it will be one of the pioneer works in the study of this new and important area of research, which we predict will fundamentally transform the study of gene expression regulation in the brain

Tight regulation of RNA metabolism is essential for normal brain function. This includes co and post-transcriptional regulation, which are extremely prevalent in neurons. Recently, circular RNAs (circRNAs), a highly abundant new type of regulatory non-coding RNA have been found across the animal kingdom. Two of these RNAs have been shown to act as miRNA sponges but no function is known for the thousands of other circRNAs, indicating the existence of a widespread layer of previously unknown gene regulation.
The present proposal aims to comprehensively determine the role and mode of actions of circRNAs in gene expression and RNA metabolism in the fly brain. We will do so by studying their biogenesis, transport, and mechanism of action, as well as by determining the roles of circRNAs in neuronal function and behaviour. Briefly, we will: 1) identify factors involved in the biogenesis, localization, and stabilization of circRNAs; 2) determine neuro-developmental, molecular, neural and behavioural phenotypes associated with down or up regulation of specific circRNAs; 3) study the molecular mechanisms of action of circRNAs: identify circRNAs that work as miRNA sponges and determine whether circRNAs can encode proteins or act as signalling molecules and 4) perform mechanistic studies in order to determine cause-effect relationships between circRNA function and brain physiology and behaviour.
The present proposal will reveal the key pathways by which circRNAs control gene expression and influence neuronal function and behaviour. Therefore it will be one of the pioneer works in the study of this new and important area of research, which we predict will fundamentally transform the study of gene expression regulation in the brain

Max ERC Funding

1 971 750 €

Duration

Start date: 2016-02-01, End date: 2021-01-31

Project acronymBRAINCOMPATH

ProjectMesoscale Brain Dynamics: Computing with Neuronal Pathways

Researcher (PI)Fritjof Helmchen

Host Institution (HI)UNIVERSITAT ZURICH

Call DetailsAdvanced Grant (AdG), LS5, ERC-2014-ADG

SummaryBrain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.

Brain computations rely on proper signal flow through the complex network of connected brain regions. Despite a wealth of anatomical and functional data – from microscopic to macroscopic scale – we still poorly understand the principles of how signal flow is routed through neuronal networks to generate appropriate behavior. Brain dynamics on the 'mesoscopic' scale, the intermediate level where local microcircuits communicate via axonal pathways, has remained a particular blind spot of research as it has been difficult to access under in vivo conditions. Here, I propose to tackle the mesoscopic level of brain dynamics both experimentally and theoretically, adopting a fresh perspective centered on neuronal pathway dynamics. Experimentally, we will utilize and further advance state-of-the-art genetic and optical techniques to create a toolbox for measuring and manipulating signal flow in pathway networks across a broad range of temporal scales. In particular, we will improve fiber-optic based methods for probing the activity of either individual or multiple neuronal pathways with high specificity. Using these tools we will set out to reveal mesoscopic brain dynamics across relevant cortical and subcortical regions in awake, behaving mice. Specifically, we will investigate sensorimotor learning for a reward-based texture discrimination task and rapid sensorimotor control during skilled locomotion. Moreover, by combining fiber-optic methods with two-photon microscopy and fMRI, respectively, we will start linking the meso-level to the micro- and macro-levels. Throughout the project, experiments will be complemented by computational approaches to analyse data, model pathway dynamics, and conceptualize a formal theory of mesoscopic dynamics. This project may transform the field by bridging the hierarchical brain levels and opening significant new avenues to assess physiological as well as pathological signal flow in the brain.

SummaryNeurodegenerative diseases (NDs) are incurable, debilitating conditions, arise mid-late in life, represent an enormous health and socioeconomic burden and no therapies exist. An enigmatic finding in NDs is the early and selective alteration in intrinsic excitability of vulnerable neurons paralleling changes in its circuitry. However, a gap in understanding exists in ND field about the cause of these alterations and whether these modifications regulate degenerative pathomechanisms. Our recent study, examining mechanisms of Purkinje cell (PC) degeneration in Spinocerebellar ataxia type 1 (SCA1) revealed that the earliest cerebellar alterations occur in the major excitatory inputs onto PCs, the climbing fibers (CFs). Based on this, we propose a novel three-step model of neurodegeneration: First, suboptimal functioning of the presynaptic inputs initiates signaling deficits in target PCs. Second, those alterations trigger maladaptive responses such as altered intrinsic PC excitability, thus amplifying pathogenic cascades. Third, at network level progressive dysfunction triggers compensatory synaptic modifications within the cerebellar circuitry. In this proposal, we will test our new hypothesis for NDs on SCA1 and this will be the first study to test circuit-dependency in NDs by selectively silencing presynaptic inputs and examining molecular responses in the postsynaptic neuron. Specifically, we will 1) Identify the dysfunctional CF associated molecular signature in PCs. 2) Elucidate mechanisms involved in altering intrinsic PC excitability. 3) Map the connectome for a structural correlate of the pathology. Using conditional mouse models, pharmacogenetics, transcriptomics, proteomics and connectomics, we will delineate molecular alterations that govern disease from compensatory alterations. Our systematic approach will not only impact SCA related therapies but the entire spectrum of NDs and has the potential to change the conceptual approach of future studies on NDs.

Neurodegenerative diseases (NDs) are incurable, debilitating conditions, arise mid-late in life, represent an enormous health and socioeconomic burden and no therapies exist. An enigmatic finding in NDs is the early and selective alteration in intrinsic excitability of vulnerable neurons paralleling changes in its circuitry. However, a gap in understanding exists in ND field about the cause of these alterations and whether these modifications regulate degenerative pathomechanisms. Our recent study, examining mechanisms of Purkinje cell (PC) degeneration in Spinocerebellar ataxia type 1 (SCA1) revealed that the earliest cerebellar alterations occur in the major excitatory inputs onto PCs, the climbing fibers (CFs). Based on this, we propose a novel three-step model of neurodegeneration: First, suboptimal functioning of the presynaptic inputs initiates signaling deficits in target PCs. Second, those alterations trigger maladaptive responses such as altered intrinsic PC excitability, thus amplifying pathogenic cascades. Third, at network level progressive dysfunction triggers compensatory synaptic modifications within the cerebellar circuitry. In this proposal, we will test our new hypothesis for NDs on SCA1 and this will be the first study to test circuit-dependency in NDs by selectively silencing presynaptic inputs and examining molecular responses in the postsynaptic neuron. Specifically, we will 1) Identify the dysfunctional CF associated molecular signature in PCs. 2) Elucidate mechanisms involved in altering intrinsic PC excitability. 3) Map the connectome for a structural correlate of the pathology. Using conditional mouse models, pharmacogenetics, transcriptomics, proteomics and connectomics, we will delineate molecular alterations that govern disease from compensatory alterations. Our systematic approach will not only impact SCA related therapies but the entire spectrum of NDs and has the potential to change the conceptual approach of future studies on NDs.

Max ERC Funding

2 000 000 €

Duration

Start date: 2017-06-01, End date: 2022-05-31

Project acronymImmuneCheckpointsAD

ProjectImmune checkpoint blockade for fighting Alzheimer’s disease

Researcher (PI)Michal EISENBACH-SCHWARTZ

Host Institution (HI)WEIZMANN INSTITUTE OF SCIENCE

Call DetailsAdvanced Grant (AdG), LS5, ERC-2016-ADG

SummaryUnderstanding, and ultimately treating Alzheimer’s disease (AD) is a major need in Western countries. Currently, there is no available treatment to modify the disease. Several pioneering discoveries made by my team, attributing a key role to systemic immunity in brain maintenance and repair, and identifying unique interface between the brain’s borders through which the immune system assists the brain, led us to our recent discovery that transient reduction of systemic immune suppression could modify disease pathology, and reverse cognitive loss in mouse models of AD (Nature Communications, 2015; Nature Medicine, 2016; Science, 2014). This discovery emphasizes that AD is not restricted to the brain, but is associated with systemic immune dysfunction. Thus, the goal of addressing numerous risk factors that go awry in the AD brain, many of which are -as yet- unknown, could be accomplished by immunotherapy, using immune checkpoint blockade directed at the Programmed-death (PD)-1 pathway, to empower the immune system. In this proposal, we will adopt our new experimental paradigm to discover mechanisms through which the immune system supports the brain, and to identify key/novel molecular and cellular processes at various stages of the disease that are responsible for cognitive decline long before neurons are lost, and whose reversal or modification is needed to mitigate AD pathology, and prevent cognitive loss. Achieving our goals requires the multidisciplinary approaches and expertise at our disposal, including state-of-the art immunological, cellular, molecular, and genomic tools. The results will pave the way for developing a novel next-generation immunotherapy, by targeting additional selective immune checkpoint pathways, or identifying a specific immune-based therapeutic target, for prevention and treatment of AD. We expect that our results will help attain the ultimate goal of converting an escalating untreatable disease into a chronic treatable one.

Understanding, and ultimately treating Alzheimer’s disease (AD) is a major need in Western countries. Currently, there is no available treatment to modify the disease. Several pioneering discoveries made by my team, attributing a key role to systemic immunity in brain maintenance and repair, and identifying unique interface between the brain’s borders through which the immune system assists the brain, led us to our recent discovery that transient reduction of systemic immune suppression could modify disease pathology, and reverse cognitive loss in mouse models of AD (Nature Communications, 2015; Nature Medicine, 2016; Science, 2014). This discovery emphasizes that AD is not restricted to the brain, but is associated with systemic immune dysfunction. Thus, the goal of addressing numerous risk factors that go awry in the AD brain, many of which are -as yet- unknown, could be accomplished by immunotherapy, using immune checkpoint blockade directed at the Programmed-death (PD)-1 pathway, to empower the immune system. In this proposal, we will adopt our new experimental paradigm to discover mechanisms through which the immune system supports the brain, and to identify key/novel molecular and cellular processes at various stages of the disease that are responsible for cognitive decline long before neurons are lost, and whose reversal or modification is needed to mitigate AD pathology, and prevent cognitive loss. Achieving our goals requires the multidisciplinary approaches and expertise at our disposal, including state-of-the art immunological, cellular, molecular, and genomic tools. The results will pave the way for developing a novel next-generation immunotherapy, by targeting additional selective immune checkpoint pathways, or identifying a specific immune-based therapeutic target, for prevention and treatment of AD. We expect that our results will help attain the ultimate goal of converting an escalating untreatable disease into a chronic treatable one.

Max ERC Funding

2 287 500 €

Duration

Start date: 2017-06-01, End date: 2022-05-31

Project acronymLearnAnx_CircAmyg

ProjectLearning and Anxiety in Amygdala-based Neural Circuits

Researcher (PI)Rony PAZ

Host Institution (HI)WEIZMANN INSTITUTE OF SCIENCE

Call DetailsConsolidator Grant (CoG), LS5, ERC-2016-COG

SummaryMajor advances were made in understanding circuits that underlie aversive emotional learning. The majority gained by using classical associative models, mainly tone/context-shock conditioning. Failure to extinguish the response or to discriminate from other safe stimuli (generalization), form two main animal models for human anxiety-disorders and post-traumatic-stress. These simple yet powerful approaches enabled cutting-edge techniques in rodents to unveil amygdala circuitry and its connectivity with the medial-prefrontal-cortex. Yet, we have less understanding of the mechanisms that underlie elaborated behavioural models of mal-adaptive behaviour, as well as less understanding of neural codes and computations in the evolutionary-expanded primate amygdala. Our lab recently embarked on exploring these venues by pioneering physiological studies of generalization and extinction protocols in primates. The goal of the current project is to develop behavioural models of complex learning and maladaptive behaviour, and then examine and shed light on the underlying computations in primate amygdala-PFC circuit. We design a novel rule-based learning task, and examine its acquisition, extinction, generalization and exploration-exploitation trade-off in dangerous environments. Specifically, the concepts of rule learning and exploration-exploitation tradeoff form novel insights and aspects of [mal-]adaptive behaviours, and will suggest new animal models of learned anxiety. We record dozens of neurons in the amygdala and prefrontal-cortex simultaneously using deep multi-contact arrays, supplemented by stimulation to address functional connectivity, and development of modelling approaches for the behaviour and neural codes. We posit that the development of more [complex] models is crucial and the next logical step in achieving translation of animal models of anxiety disorders, as well as in understanding basic mechanisms behind the rich repertoire of emotional behaviours.

Major advances were made in understanding circuits that underlie aversive emotional learning. The majority gained by using classical associative models, mainly tone/context-shock conditioning. Failure to extinguish the response or to discriminate from other safe stimuli (generalization), form two main animal models for human anxiety-disorders and post-traumatic-stress. These simple yet powerful approaches enabled cutting-edge techniques in rodents to unveil amygdala circuitry and its connectivity with the medial-prefrontal-cortex. Yet, we have less understanding of the mechanisms that underlie elaborated behavioural models of mal-adaptive behaviour, as well as less understanding of neural codes and computations in the evolutionary-expanded primate amygdala. Our lab recently embarked on exploring these venues by pioneering physiological studies of generalization and extinction protocols in primates. The goal of the current project is to develop behavioural models of complex learning and maladaptive behaviour, and then examine and shed light on the underlying computations in primate amygdala-PFC circuit. We design a novel rule-based learning task, and examine its acquisition, extinction, generalization and exploration-exploitation trade-off in dangerous environments. Specifically, the concepts of rule learning and exploration-exploitation tradeoff form novel insights and aspects of [mal-]adaptive behaviours, and will suggest new animal models of learned anxiety. We record dozens of neurons in the amygdala and prefrontal-cortex simultaneously using deep multi-contact arrays, supplemented by stimulation to address functional connectivity, and development of modelling approaches for the behaviour and neural codes. We posit that the development of more [complex] models is crucial and the next logical step in achieving translation of animal models of anxiety disorders, as well as in understanding basic mechanisms behind the rich repertoire of emotional behaviours.

Max ERC Funding

2 000 000 €

Duration

Start date: 2017-09-01, End date: 2022-08-31

Project acronymMacroStability

ProjectStability and dynamics at different spatial scales: From physiology to Alzheimer's degeneration

Researcher (PI)Inna Slutsky

Host Institution (HI)TEL AVIV UNIVERSITY

Call DetailsConsolidator Grant (CoG), LS5, ERC-2016-COG

SummaryHow neuronal circuits maintain the balance between stability and plasticity in a constantly changing environment remains one of the most fundamental questions in neuroscience. Empirical and theoretical studies suggest that homeostatic negative feedback mechanisms operate to stabilize the function of a system at a set point level of activity. While extensive research uncovered diverse homeostatic mechanisms that maintain activity of neural circuits at extended timescales, several key questions remain open. First, what are the basic principles and the molecular machinery underlying invariant population dynamics of neural circuits, composed from intrinsically unstable activity patterns of individual neurons? Second, is homeostatic regulation compromised in Alzheimer's disease (AD) and do homeostatic failures lead to aberrant brain activity and memory decline, the overlapping phenotypes of AD and many other distinct neurodegenerative disorders? And finally, how do homeostatic systems operate in vivo under experience-dependent changes in firing rates and patterns?
To target these questions, we have developed an integrative approach to study the relationships between ongoing spiking activity of individual neurons and neuronal populations, signaling processes at the level of single synapses and neuronal meta-plasticity. We will focus on hippocampal circuitry and combine ex vivo electrophysiology, single- and two-photon excitation imaging, time-resolved fluorescence microscopy and molecular biology, together with longitudinal monitoring of activity from large populations of hippocampal neurons in freely behaving mice. Utilizing these state-of-the-art approaches, we will determine how firing stability is maintained at different spatial scales and what are the mechanisms leading to destabilization of firing patterns in AD-related context. The proposed research will elucidate fundamental principles of neuronal function and offer conceptual insights into AD pathophysiology.

How neuronal circuits maintain the balance between stability and plasticity in a constantly changing environment remains one of the most fundamental questions in neuroscience. Empirical and theoretical studies suggest that homeostatic negative feedback mechanisms operate to stabilize the function of a system at a set point level of activity. While extensive research uncovered diverse homeostatic mechanisms that maintain activity of neural circuits at extended timescales, several key questions remain open. First, what are the basic principles and the molecular machinery underlying invariant population dynamics of neural circuits, composed from intrinsically unstable activity patterns of individual neurons? Second, is homeostatic regulation compromised in Alzheimer's disease (AD) and do homeostatic failures lead to aberrant brain activity and memory decline, the overlapping phenotypes of AD and many other distinct neurodegenerative disorders? And finally, how do homeostatic systems operate in vivo under experience-dependent changes in firing rates and patterns?
To target these questions, we have developed an integrative approach to study the relationships between ongoing spiking activity of individual neurons and neuronal populations, signaling processes at the level of single synapses and neuronal meta-plasticity. We will focus on hippocampal circuitry and combine ex vivo electrophysiology, single- and two-photon excitation imaging, time-resolved fluorescence microscopy and molecular biology, together with longitudinal monitoring of activity from large populations of hippocampal neurons in freely behaving mice. Utilizing these state-of-the-art approaches, we will determine how firing stability is maintained at different spatial scales and what are the mechanisms leading to destabilization of firing patterns in AD-related context. The proposed research will elucidate fundamental principles of neuronal function and offer conceptual insights into AD pathophysiology.

Max ERC Funding

2 000 000 €

Duration

Start date: 2017-10-01, End date: 2022-09-30

Project acronymMCircuits

ProjectConnectivity, plasticity and function of an olfactory memory circuit

SummaryThe brain accumulates knowledge by experience-driven modifications of neuronal connectivity and creates models of the world that enable intelligent behavior. It is thought that these processes are based on autoassociative mechanisms of circuit plasticity. However, direct tests of these fundamental concepts are difficult because they require dense reconstructions of neuronal wiring diagrams. We will dissect structural and functional mechanisms of autoassociative memory in telencephalic area Dp of adult zebrafish, the homologue of olfactory cortex. The small size of the zebrafish brain provides essential advantages for exhaustive measurements of neuronal activity and connectivity patterns. Key predictions of theoretical models will be examined by analyzing effects of odor discrimination learning on the dynamics and stability of odor representations in Dp. The underlying structural circuit modifications will be examined in the same brains by circuit reconstruction using serial block face scanning electron microscopy (SBEM). The dense reconstruction of neuronal ensembles responding to learned and novel odors will allow for advanced analyses of structure-function relationships that have not been possible so far. Odor stimulation in a virtual environment will be combined with optogenetic activation or silencing of neuromodulatory inputs to write and disrupt specific olfactory memories and to analyze the effects on behavior and connectivity. The underlying cellular mechanisms of synaptic plasticity and metaplasticity will be examined by electrophysiology, imaging and optogenetic approaches. Mutants will be used to assess effects of disease-related mutations on circuit structure, function and plasticity. These mechanistic analyses are guided by theoretical models, expected to generate direct insights into elementary computations underlying higher brain functions, and likely to uncover causal links between circuit connectivity, circuit function and behavior.

The brain accumulates knowledge by experience-driven modifications of neuronal connectivity and creates models of the world that enable intelligent behavior. It is thought that these processes are based on autoassociative mechanisms of circuit plasticity. However, direct tests of these fundamental concepts are difficult because they require dense reconstructions of neuronal wiring diagrams. We will dissect structural and functional mechanisms of autoassociative memory in telencephalic area Dp of adult zebrafish, the homologue of olfactory cortex. The small size of the zebrafish brain provides essential advantages for exhaustive measurements of neuronal activity and connectivity patterns. Key predictions of theoretical models will be examined by analyzing effects of odor discrimination learning on the dynamics and stability of odor representations in Dp. The underlying structural circuit modifications will be examined in the same brains by circuit reconstruction using serial block face scanning electron microscopy (SBEM). The dense reconstruction of neuronal ensembles responding to learned and novel odors will allow for advanced analyses of structure-function relationships that have not been possible so far. Odor stimulation in a virtual environment will be combined with optogenetic activation or silencing of neuromodulatory inputs to write and disrupt specific olfactory memories and to analyze the effects on behavior and connectivity. The underlying cellular mechanisms of synaptic plasticity and metaplasticity will be examined by electrophysiology, imaging and optogenetic approaches. Mutants will be used to assess effects of disease-related mutations on circuit structure, function and plasticity. These mechanistic analyses are guided by theoretical models, expected to generate direct insights into elementary computations underlying higher brain functions, and likely to uncover causal links between circuit connectivity, circuit function and behavior.

Max ERC Funding

2 495 839 €

Duration

Start date: 2017-10-01, End date: 2022-09-30

Project acronymMultiScaleNeurovasc

ProjectQuantifying the structure-function of the neurovascular interface: from micro-circuits to large-scale functional organization

Researcher (PI)Pablo Blinder

Host Institution (HI)TEL AVIV UNIVERSITY

Call DetailsStarting Grant (StG), LS5, ERC-2014-STG

SummaryNeuronal computations in the brain require a high metabolic budget yet the brain has extremely limited resources; calling for an on-demand, robust supply system to deliver nutrients to active regions. In most cases, neuronal activity results in an increase in blood flow to the active area, a phenomenon called functional hyperaemia. This coupling between neuronal and vascular activtuy underpins the mechanism enabling fMRI to map neuronal activity based on vascular dynamics; further, malfunction of the cellular players involved in coupling is now considered to play a key role in otherwise classically defined neurodegenerative diseases. We lack a concise description of the inner workings of this mechanism and a thorough quantitative description of the neuro-gila-vascular interface; issues that are best addressed by an investigation into the cellular mechanisms, the temporal dynamics and multi-scale spatial organization governing neurovascular coupling. My long-term goal is to provide a unified theory to encapsulate our knowledge on neurovascular coupling. Here, I hypothesize that functional hyperaemia results from the constant integration of vasoactive cues with region-dependent coupling emerging from different neuro-glia-vascular microcircuits, nuances in afferent wiring into vascular contractile elements and/or neuronal activity patterns. I will test this hypothesis with a multi-faceted correlative approach combining: two-photon awake imaging of cellular and vascular dynamics to obtain physiological data unaffected by anaesthetics; super-resolution structural imaging of intact volumes to map the fine details of micro-circuit structure; array-tomography to map in situ the neurovascular signalling machinery and novel optogenic tools to manipulate several of its specific components. I expect to offer a revolutionary mechanistic insight into one of the most basic and fundamental physiological processes behind the structure and function of the brain.

Neuronal computations in the brain require a high metabolic budget yet the brain has extremely limited resources; calling for an on-demand, robust supply system to deliver nutrients to active regions. In most cases, neuronal activity results in an increase in blood flow to the active area, a phenomenon called functional hyperaemia. This coupling between neuronal and vascular activtuy underpins the mechanism enabling fMRI to map neuronal activity based on vascular dynamics; further, malfunction of the cellular players involved in coupling is now considered to play a key role in otherwise classically defined neurodegenerative diseases. We lack a concise description of the inner workings of this mechanism and a thorough quantitative description of the neuro-gila-vascular interface; issues that are best addressed by an investigation into the cellular mechanisms, the temporal dynamics and multi-scale spatial organization governing neurovascular coupling. My long-term goal is to provide a unified theory to encapsulate our knowledge on neurovascular coupling. Here, I hypothesize that functional hyperaemia results from the constant integration of vasoactive cues with region-dependent coupling emerging from different neuro-glia-vascular microcircuits, nuances in afferent wiring into vascular contractile elements and/or neuronal activity patterns. I will test this hypothesis with a multi-faceted correlative approach combining: two-photon awake imaging of cellular and vascular dynamics to obtain physiological data unaffected by anaesthetics; super-resolution structural imaging of intact volumes to map the fine details of micro-circuit structure; array-tomography to map in situ the neurovascular signalling machinery and novel optogenic tools to manipulate several of its specific components. I expect to offer a revolutionary mechanistic insight into one of the most basic and fundamental physiological processes behind the structure and function of the brain.

Max ERC Funding

1 500 000 €

Duration

Start date: 2015-06-01, End date: 2020-05-31

Project acronymNeurogenesisCode

ProjectDeciphering the role of adult neurogenesis in hippocampal memory codes by optically imaging neuronal activity in freely behaving mice

Researcher (PI)Yaniv Ziv

Host Institution (HI)WEIZMANN INSTITUTE OF SCIENCE

Call DetailsStarting Grant (StG), LS5, ERC-2014-STG

SummaryThe hippocampal dentate gyrus (DG) is one of the few areas in the adult mammalian brain that exhibits neurogenesis, the continuous generation of new neurons. Much evidence indicates that adult neurogenesis contributes to hippocampal-dependent cognition, but the nature of this contribution remains elusive. I envisioned that the clearest path towards understanding the function of adult neurogenesis would be to reveal the changes that occur in the coding properties of DG neurons throughout their development, and the changes that these neurons impose on neural codes generated by the hippocampus. The study of such coding dynamics requires longitudinal recordings of neuronal ensembles in both the DG and CA1 over periods of weeks, since this is the timescale on which new DG neurons mature. Until recently, however, it has been technically impossible to obtain such data. This urgent need drove me to develop a new method, which allows for the optical recording of Ca2+ dynamics from up to 1,200 of the same genetically defined neurons in the hippocampus of freely behaving mice for periods of months. Here, I propose to combine this method with established tools for manipulation of neurogenesis rates or newborn neuron activity, to determine how neurogenesis contributes to coding dynamics in downstream CA1 while mice repeatedly explore familiar environments or preform a long-term memory task. Furthermore, we will establish time-lapse imaging of Ca2+ dynamics in populations of newborn DG neurons while mice perform tasks that engage the DG, and find how newborn neuron coding properties evolve as a function of their maturation. Our work will advance the understanding of how the hippocampus supports long-term memory by resolving fundamental questions that pertain to a nearly unexplored facet of memory: how memory codes change with time, while their behavioral manifestations persist.

The hippocampal dentate gyrus (DG) is one of the few areas in the adult mammalian brain that exhibits neurogenesis, the continuous generation of new neurons. Much evidence indicates that adult neurogenesis contributes to hippocampal-dependent cognition, but the nature of this contribution remains elusive. I envisioned that the clearest path towards understanding the function of adult neurogenesis would be to reveal the changes that occur in the coding properties of DG neurons throughout their development, and the changes that these neurons impose on neural codes generated by the hippocampus. The study of such coding dynamics requires longitudinal recordings of neuronal ensembles in both the DG and CA1 over periods of weeks, since this is the timescale on which new DG neurons mature. Until recently, however, it has been technically impossible to obtain such data. This urgent need drove me to develop a new method, which allows for the optical recording of Ca2+ dynamics from up to 1,200 of the same genetically defined neurons in the hippocampus of freely behaving mice for periods of months. Here, I propose to combine this method with established tools for manipulation of neurogenesis rates or newborn neuron activity, to determine how neurogenesis contributes to coding dynamics in downstream CA1 while mice repeatedly explore familiar environments or preform a long-term memory task. Furthermore, we will establish time-lapse imaging of Ca2+ dynamics in populations of newborn DG neurons while mice perform tasks that engage the DG, and find how newborn neuron coding properties evolve as a function of their maturation. Our work will advance the understanding of how the hippocampus supports long-term memory by resolving fundamental questions that pertain to a nearly unexplored facet of memory: how memory codes change with time, while their behavioral manifestations persist.